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Carisbamate in Adult & Pediatric Subjects With Lennox-Gastaut Syndrome

Primary Purpose

Lennox Gastaut Syndrome

Status
Completed
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Carisbamate
Sponsored by
SK Life Science, Inc.
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional basic science trial for Lennox Gastaut Syndrome focused on measuring LGS

Eligibility Criteria

2 Years - undefined (Child, Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  1. Diagnosis of LGS as evidenced by the following:

    1. More than 1 type of generalized seizure, including drop seizures (atonic, tonic, or myoclonic), for ≥6 months before Visit 1
    2. Previous electroencephalogram reporting diagnostic criteria for LGS (abnormal background activity accompanied by slow spike-and-wave pattern <2.5 Hz)
  2. Male or female aged ≥2 years at the time of consent
  3. Aged <11 years at the onset of LGS
  4. Written informed consent signed by the subject or legal guardian prior to entering the study in accordance with the ICH GCP guidelines. Age appropriate assent will be obtained for children and adolescents. If the written informed consent is provided by the legal guardian because the subject is unable to do so, a written or verbal assent from the subject must also be obtained.
  5. Receiving 1 to 3 concomitant AEDs at a stable dose for ≥30 days before Visit 1 (vagal nerve stimulation [VNS] and ketogenic diet, stable and ongoing for ≥30 days before Visit 1, do not count as AEDs)
  6. In the Investigator's opinion, parents or caregivers must be able to report accurate seizure assessments during the screening and study periods and subjects must be able to ingest study drug
  7. Body weight ≥8 kg for subjects enrolled in Cohort IV
  8. Subjects with an implanted vagal nerve stimulator will be allowed if the vagal nerve stimulator was implanted at least 5 months prior to Visit 1 (Screening) and the stimulator parameters are not changed for 30 days prior to Visit 1 and for the duration of the study
  9. Subjects following a ketogenic diet will be allowed as long as the diet has been stable for at least 30 days prior to Visit 1 (Screening) and will remain stable for the duration of the study.

Exclusion Criteria:

  1. Progressive neurological disease
  2. Prior treatment with carisbamate
  3. Evidence of clinically significant disease or any medical condition that would compromise the subject's ability to safely complete the study
  4. Any surgical or medical condition that may interfere with the absorption, distribution, metabolism, or excretion of the investigational medicine product
  5. Acute disease state (e.g., nausea, vomiting, fever, or diarrhea) within 7 days before Day 1
  6. Scheduled for surgery during the study
  7. Ketogenic diet or VNS, unless stable and ongoing for ≥30 days before Visit 1
  8. Treatment with an investigational drug or device ≥30 days before Visit 1
  9. Status epilepticus within 12 weeks of Visit 1
  10. Felbamate for <1 year (subjects taking felbamate for ≥1 year must have a stable dose for 60 days before Visit 1)
  11. Concomitant use of vigabatrin or other medications known to be inducers of CYP3A
  12. Use of drugs known as UGT inducers, e.g., carbamazepine, phenytoin, phenobarbital, primidone, or oxcarbazepine
  13. Use of cannabinoids (any form), cannabidiols, or medical or recreational marijuana
  14. Use of any prescription or non-prescription drugs, including over-the-counter medication, non-routine vitamins and herbal products within 2 weeks prior to study drug administration unless discussed and agreed with the Sponsor's medical representative in writing. (Medication used to treat TEAEs does not lead to a compulsory exclusion of subjects.)
  15. Consumption of any caffeine-containing products (e.g., coffee, tea, chocolate, or soda) or alcoholic beverages within 48 hours before Day 1 and until the end of each PK sampling period
  16. Consumption of grapefruit or grapefruit-containing products within 72 hours before Day 1 and until the end of each PK sampling period
  17. History of any serious drug-induced hypersensitivity reaction (including but not limited to Stevens Johnson syndrome, toxic epidermal necrolysis, Drug Rash with Eosinophilia and Systemic Symptoms [DRESS]) or any drug-related rash requiring hospitalization
  18. History of AED-associated rash that involved conjunctiva or mucosae
  19. History of more than one non-serious drug-related hypersensitivity reaction that required discontinuation of the medication
  20. Significant clinical laboratory abnormalities, including elevation of serum AST or ALT more than 1.5 times ULN for age group, or any elevation of bilirubin or creatinine about the ULN for age group at Screening
  21. Any clinically-significant uncontrolled medical illness, including hepatic or renal failure, ischemic disease, human immunodeficiency virus (HIV) infection, active sexually-transmitted disease (STD), active viral hepatitis, malignancy, or any disorder that in the judgement of the investigator places the subject at risk by participation in this study
  22. History of drug-induced liver injury
  23. Positive urine screen of drugs of abuse (if not due to concomitant medication, e.g. benzodiazepines as hypnotics) for adult and adolescent subjects.
  24. Adrenocorticotropic hormone within the 6 months before Visit 1
  25. History of anoxic episodes requiring resuscitation within 6 months before Visit 1, drug or alcohol dependency or abuse within approximately the last 2 years, or use of illegal recreational drugs
  26. Females who are breastfeeding or pregnant at Screening or Baseline or who are of reproductive age and do not agree to be abstinent or to use highly effective contraception
  27. Intermittent use of benzodiazepine of >4 single administrations in the month before Visit 1
  28. Clinically significant abnormality on the 12-lead ECG at Screening, and any child or adolescent with a QTcF less than 330 ms or greater than 450 ms
  29. Congenital short QT syndrome
  30. Hypersensitivity to the study drug or any of the excipients
  31. Psychotic disorder(s) or unstable recurrent affective disorder(s)

Sites / Locations

  • Johns Hopkins Hospital
  • Dartmouth-Hitchcock Medical Center
  • Duke Health
  • Oregon Health and Science University
  • Hospital of the University of Pennsylvania
  • The University of Utah School of Medicine - Primary Children's Hospital (Primary Children's Medical Center)
  • UW Valley Medical Center

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Experimental

Experimental

Experimental

Experimental

Arm Label

Cohort I

Cohort II

Cohort III

Cohort IV

Arm Description

Subjects ≥18 years of age. Carisbamate, 200 mg, will be administered on Day 1 and 2 of the single-dose period. Carisbamate will be administered at 100 mg twice daily (BID) during the multiple-dose period.

Subjects 12 to <18 years of age. Carisbamate, 140 mg, will be administered on Day 1 and 2 of the single dose period. Carisbamate will be administered at 70 mg twice daily (BID) during the multiple-dose period.

Subjects 6 to <12 years of age. Carisbamate, 60 mg, will be administered on Day 1 and 2 of the single dose period. Carisbamate will be administered at 30 mg twice daily (BID) during the multiple-dose period.

Subjects 2 to <6 years of age. The starting doses for the single dose and multiple-dose periods will be based on the PK and safety results of the first 3 cohorts.

Outcomes

Primary Outcome Measures

The area under the curve (AUC) of carisbamate after a single and multiple doses of carisbamate.
Safety Assessment
The maximum plasma concentration (Cmax) after a single and multiple doses of carisbamate.
Safety assessment

Secondary Outcome Measures

Safety - adverse events (AEs) reporting after a single and multiple doses of carisbamate.
Adverse event assessment for seriousness (yes, no), severity (mild, moderate, severe), affect on carisbamate dosing (increase, reduced, interrupted, withdrawn, no change), and outcome (recovered/resolved,recovered/resolved with sequelae, recovering/resolving, not recovered/not resolved, fatal or unknown).

Full Information

First Posted
October 16, 2018
Last Updated
May 26, 2023
Sponsor
SK Life Science, Inc.
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1. Study Identification

Unique Protocol Identification Number
NCT03731715
Brief Title
Carisbamate in Adult & Pediatric Subjects With Lennox-Gastaut Syndrome
Official Title
Phase I, Open-Label, Pharmacokinetic, Dose Escalation Study of Carisbamate in Adult and Pediatric Subjects With Lennox-Gastaut Syndrome
Study Type
Interventional

2. Study Status

Record Verification Date
May 2023
Overall Recruitment Status
Completed
Study Start Date
February 7, 2019 (Actual)
Primary Completion Date
May 23, 2022 (Actual)
Study Completion Date
June 29, 2022 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
SK Life Science, Inc.

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

Brief Summary
This is an open-label, multi-center study of carisbamate in adult and pediatric subjects with LGS, with single- and multiple-dose PK assessments from Days 1 through 73. There will be a Screening Period of up to 28 days and a Treatment Period of 87 days.
Detailed Description
A total of 24 subjects are planned: 6 subjects in each of 4 cohorts: Cohort I (≥18 years), Cohort II (12 to <18 years), Cohort III (6 to <12 years), and Cohort IV (2 to <6 years). For Cohorts I and II, PK assessments of carisbamate, S-enantiomer and its R-enantiomer plasma concentrations, will be conducted on Days 1, 2 and 3 of the single dose period at pre-dose and 0.5, 1, 1.5, 2, 4, 6, 8, 12, 24, and 48 hours after dosing and on Day 17 of the multiple-dose period at pre dose and 0.5, 1, 1.5, 2, 4, 6, 8, and 12 hours after dosing; trough samples will be collected on Days 45 and 73 of the dose-adjustment period. For Cohort III, PK assessments of carisbamate, S-enantiomer and its R-enantiomer plasma concentrations will be conducted on Days 1, 2 and 3 of the single dose period at pre dose and 0.5, 1, 2, 4, 6, 8, 12, 24, and 48 hours after dosing and on Day 17 of the multiple-dose period at pre-dose and 2 hours after dosing; trough samples will be collected on Days 45 and 73 of the dose-adjustment period. For Cohort IV, a sparse PK sampling approach will be used, and the time of PK sampling time will be based on the PK results from the other cohorts. A maximum of 2 to 4 time points on each day (1 and 17) will be collected. Safety assessments include adverse event (AE) and concomitant medication reporting, clinical laboratory testing, vital sign measurements, 12 lead electrocardiograms (ECGs), physical examinations, and neurologic examinations.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Lennox Gastaut Syndrome
Keywords
LGS

7. Study Design

Primary Purpose
Basic Science
Study Phase
Phase 1
Interventional Study Model
Parallel Assignment
Model Description
Open-label
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
18 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Cohort I
Arm Type
Experimental
Arm Description
Subjects ≥18 years of age. Carisbamate, 200 mg, will be administered on Day 1 and 2 of the single-dose period. Carisbamate will be administered at 100 mg twice daily (BID) during the multiple-dose period.
Arm Title
Cohort II
Arm Type
Experimental
Arm Description
Subjects 12 to <18 years of age. Carisbamate, 140 mg, will be administered on Day 1 and 2 of the single dose period. Carisbamate will be administered at 70 mg twice daily (BID) during the multiple-dose period.
Arm Title
Cohort III
Arm Type
Experimental
Arm Description
Subjects 6 to <12 years of age. Carisbamate, 60 mg, will be administered on Day 1 and 2 of the single dose period. Carisbamate will be administered at 30 mg twice daily (BID) during the multiple-dose period.
Arm Title
Cohort IV
Arm Type
Experimental
Arm Description
Subjects 2 to <6 years of age. The starting doses for the single dose and multiple-dose periods will be based on the PK and safety results of the first 3 cohorts.
Intervention Type
Drug
Intervention Name(s)
Carisbamate
Other Intervention Name(s)
YKP509
Intervention Description
An oral liquid formulation (20 mg/mL) of carisbamate (S-carisbamate)
Primary Outcome Measure Information:
Title
The area under the curve (AUC) of carisbamate after a single and multiple doses of carisbamate.
Description
Safety Assessment
Time Frame
Days 1-3, Day 17
Title
The maximum plasma concentration (Cmax) after a single and multiple doses of carisbamate.
Description
Safety assessment
Time Frame
Days 1-3, Day 17
Secondary Outcome Measure Information:
Title
Safety - adverse events (AEs) reporting after a single and multiple doses of carisbamate.
Description
Adverse event assessment for seriousness (yes, no), severity (mild, moderate, severe), affect on carisbamate dosing (increase, reduced, interrupted, withdrawn, no change), and outcome (recovered/resolved,recovered/resolved with sequelae, recovering/resolving, not recovered/not resolved, fatal or unknown).
Time Frame
Days 1-87

10. Eligibility

Sex
All
Minimum Age & Unit of Time
2 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Diagnosis of LGS as evidenced by the following: More than 1 type of generalized seizure, including drop seizures (atonic, tonic, or myoclonic), for ≥6 months before Visit 1 Previous electroencephalogram reporting diagnostic criteria for LGS (abnormal background activity accompanied by slow spike-and-wave pattern <2.5 Hz) Male or female aged ≥2 years at the time of consent Aged <11 years at the onset of LGS Written informed consent signed by the subject or legal guardian prior to entering the study in accordance with the ICH GCP guidelines. Age appropriate assent will be obtained for children and adolescents. If the written informed consent is provided by the legal guardian because the subject is unable to do so, a written or verbal assent from the subject must also be obtained. Receiving 1 to 3 concomitant AEDs at a stable dose for ≥30 days before Visit 1 (vagal nerve stimulation [VNS] and ketogenic diet, stable and ongoing for ≥30 days before Visit 1, do not count as AEDs) In the Investigator's opinion, parents or caregivers must be able to report accurate seizure assessments during the screening and study periods and subjects must be able to ingest study drug Body weight ≥8 kg for subjects enrolled in Cohort IV Subjects with an implanted vagal nerve stimulator will be allowed if the vagal nerve stimulator was implanted at least 5 months prior to Visit 1 (Screening) and the stimulator parameters are not changed for 30 days prior to Visit 1 and for the duration of the study Subjects following a ketogenic diet will be allowed as long as the diet has been stable for at least 30 days prior to Visit 1 (Screening) and will remain stable for the duration of the study. Exclusion Criteria: Progressive neurological disease Prior treatment with carisbamate Evidence of clinically significant disease or any medical condition that would compromise the subject's ability to safely complete the study Any surgical or medical condition that may interfere with the absorption, distribution, metabolism, or excretion of the investigational medicine product Acute disease state (e.g., nausea, vomiting, fever, or diarrhea) within 7 days before Day 1 Scheduled for surgery during the study Ketogenic diet or VNS, unless stable and ongoing for ≥30 days before Visit 1 Treatment with an investigational drug or device ≥30 days before Visit 1 Status epilepticus within 12 weeks of Visit 1 Felbamate for <1 year (subjects taking felbamate for ≥1 year must have a stable dose for 60 days before Visit 1) Concomitant use of vigabatrin or other medications known to be inducers of CYP3A Use of drugs known as UGT inducers, e.g., carbamazepine, phenytoin, phenobarbital, primidone, or oxcarbazepine Use of cannabinoids (any form), cannabidiols, or medical or recreational marijuana Use of any prescription or non-prescription drugs, including over-the-counter medication, non-routine vitamins and herbal products within 2 weeks prior to study drug administration unless discussed and agreed with the Sponsor's medical representative in writing. (Medication used to treat TEAEs does not lead to a compulsory exclusion of subjects.) Consumption of any caffeine-containing products (e.g., coffee, tea, chocolate, or soda) or alcoholic beverages within 48 hours before Day 1 and until the end of each PK sampling period Consumption of grapefruit or grapefruit-containing products within 72 hours before Day 1 and until the end of each PK sampling period History of any serious drug-induced hypersensitivity reaction (including but not limited to Stevens Johnson syndrome, toxic epidermal necrolysis, Drug Rash with Eosinophilia and Systemic Symptoms [DRESS]) or any drug-related rash requiring hospitalization History of AED-associated rash that involved conjunctiva or mucosae History of more than one non-serious drug-related hypersensitivity reaction that required discontinuation of the medication Significant clinical laboratory abnormalities, including elevation of serum AST or ALT more than 1.5 times ULN for age group, or any elevation of bilirubin or creatinine about the ULN for age group at Screening Any clinically-significant uncontrolled medical illness, including hepatic or renal failure, ischemic disease, human immunodeficiency virus (HIV) infection, active sexually-transmitted disease (STD), active viral hepatitis, malignancy, or any disorder that in the judgement of the investigator places the subject at risk by participation in this study History of drug-induced liver injury Positive urine screen of drugs of abuse (if not due to concomitant medication, e.g. benzodiazepines as hypnotics) for adult and adolescent subjects. Adrenocorticotropic hormone within the 6 months before Visit 1 History of anoxic episodes requiring resuscitation within 6 months before Visit 1, drug or alcohol dependency or abuse within approximately the last 2 years, or use of illegal recreational drugs Females who are breastfeeding or pregnant at Screening or Baseline or who are of reproductive age and do not agree to be abstinent or to use highly effective contraception Intermittent use of benzodiazepine of >4 single administrations in the month before Visit 1 Clinically significant abnormality on the 12-lead ECG at Screening, and any child or adolescent with a QTcF less than 330 ms or greater than 450 ms Congenital short QT syndrome Hypersensitivity to the study drug or any of the excipients Psychotic disorder(s) or unstable recurrent affective disorder(s)
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Marc Kamin, MD
Organizational Affiliation
SK Life Science, Inc.
Official's Role
Study Director
Facility Information:
Facility Name
Johns Hopkins Hospital
City
Baltimore
State/Province
Maryland
ZIP/Postal Code
21210
Country
United States
Facility Name
Dartmouth-Hitchcock Medical Center
City
Lebanon
State/Province
New Hampshire
ZIP/Postal Code
03756
Country
United States
Facility Name
Duke Health
City
Durham
State/Province
North Carolina
ZIP/Postal Code
27710
Country
United States
Facility Name
Oregon Health and Science University
City
Portland
State/Province
Oregon
ZIP/Postal Code
97239
Country
United States
Facility Name
Hospital of the University of Pennsylvania
City
Philadelphia
State/Province
Pennsylvania
ZIP/Postal Code
19104
Country
United States
Facility Name
The University of Utah School of Medicine - Primary Children's Hospital (Primary Children's Medical Center)
City
Salt Lake City
State/Province
Utah
ZIP/Postal Code
84113
Country
United States
Facility Name
UW Valley Medical Center
City
Renton
State/Province
Washington
ZIP/Postal Code
98055
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
No

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Carisbamate in Adult & Pediatric Subjects With Lennox-Gastaut Syndrome

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